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Aging in a statistical sense is the increasing probability of death with increasing time of an organism’s existence (1, 2). Can we extrapolate this to self-regenerating tissues and most particularly to the stem cells that drive the replenishment of lost and damaged cells throughout life? To be succinct, how close is the linkage between the vitality of the stem cell population and organismal longevity? These questions are currently without clear answers and the nature of the linkage, if any, is likely to be complicated, but is nonetheless conceptually compelling. However, in the most straightforward and blunt analysis, limiting numbers of hematopoietic stem cells, for example, resulting in aplastic anemia is an infrequent cause of death (3). Moreover, the hallmark property that distinguishes stem cells from most other somatic cells, their ability to self-replicate, in theory should provide a life-long supply. It was shown many years ago that hematopoietic stem cells could be transplanted into myeloablated recipients and continue to produce large numbers of differentiated blood cells over a time period that greatly exceeded the lifespan of the donor mouse (4). Serial transplants, in which an original bone marrow graft is passaged through a series of recipients, put even greater demands on stem cell proliferation and differentiation and thus demonstrate the tremendous regenerative potential of these cells. However, the number of transplant iterations that may be carried out is limited using marrow from young mice (5, 6), and further reduced if donors are old (6, 7). In fact it is restricted to less than five, depending on mouse strain, and although it has been argued that the limitation is not so much a result of diminished stem cell potential as in the transplantation procedure itself (8), it is now clear that stem cells’ regenerative properties diminish during the enforced stress of transplantation and during aging (9–15). Thus, there are growing indications that decrements in stem cell numbers and perhaps more importantly, function, play a role in the aging process. For example, it is well known that age-related decline in the immune system is associated with diminished ability to stave off infection and probably accounts for diminished surveillance and killing of malignant cells (16–21). Whether or not the primary lesion for immune decline resides, at least partially, at the stem cell level is without a definitive answer. For example, in the case of the involution of the thymus, more complicated scenarios, including effects on the thymic epithelium, have been invoked (21).

The Western population is aging. Currently, individuals aged 65 and older represent 12% of the US population and by the year 2030 they are expected to represent 20% (1). The segment of the population increasing more rapidly than any other involves individuals over 85, the so called “oldest old.” The mean life expectancy of the population was around 60 years in 1900, is currently 80 for women and 76 for man and is expected to rise to 84 and 80, respectively, in 2030 (1).

This epidemic presents medical and social implications. Aging is associated with increased prevalence of chronic diseases, disabilities and functional dependence, that in turn lead to increased demand for medical services as well as for social services and care-giving (2, 3).While aging cannot be prevented, the complications of aging may be preventable or at least delayed. Compression of morbidity may prolong the independence and improve the quality of life of the older aged person and at the same time it may minimize the management-related costs (4, 5).

This chapter explores the interactions of anemia and aging that are of interest for at least three reasons. First, incidence and prevalence of anemia increase with aging (6–8). Second anemia may represent the early sign of an underlying serious disease such as cancer, hypothyroidism or malabsorption (6). Third, anemia itself is associated with increased mortality and disability (7). It is reasonable to expect that prompt and effective management of anemia may help compress the aging-related morbidity.

Iron deficiency, and particularly iron deficiency as a cause of anemia, is one of the commonest nutritional deficiencies in man. According to the NHANES studies of 1999–2000, there was a 4% incidence of iron deficiency and a 2% incidence of iron deficiency anemia (IDA) in males over the age of 70 (1). In females of a comparable age, it was estimated that 7% were iron deficient and 2% actually had IDA. Iron deficiency is the most common nutritional deficiency in both developed and underdeveloped countries and, worldwide, nearly one-half billion individuals suffer from iron deficiency. [An excellent review of iron metabolism in man can be found in (2); and an in-depth overview of all aspects of iron metabolism can be found in (3).]

The anemia of chronic inflammation (ACI) is one of the major causes of hypoproliferative anemia in man. ACI can be associated with inflammation of any type (Table 4.1). In each case, the associations represent a form of inflammation and cytokine release, whether infectious or not. Even with simple tissue injury, such as myocardial infarction or surgery, there is an inflammatory response in the process of wound repair.

There are four major mechanisms that contribute to the anemia of chronic inflammation.

Anemia is a well-known complication of chronic kidney disease (CKD) that develops as kidney function declines. In most patients with CKD, the glomerular filtration rate (GFR) declines over time, and as it does so, anemia becomes more prevalent and more severe. The relationship between anemia and CKD in elderly subjects is not as well defined as in younger populations. As discussed elsewhere in this book, the optimal definition of anemia in older subjects is a matter of some debate (1,2). Also, the estimation of the level of kidney function in older individuals poses some special problems that will be discussed.

Since the association of anemia and reduced kidney function in the general (i.e., non-elderly) population is discussed thoroughly elsewhere (3–5), this chapter focuses on specific issues pertinent to the assessment of kidney function in the elderly, the diagnosis and impact of CKD-related anemia in the elderly, and treatment of anemia in elderly subjects with CKDrelated anemia.

Long-term care refers to a heterogeneous spectrum of facilities and health-related services that range from home nursing services to residential care and skilled nursing facilities, so-called nursing homes. Although the services eligible for Medicare coverage are defined by CMS, the clinical and demographic mix in facilities, even of the same level of care, is highly variable. The shifting health care environment has led to a shift towards increasing acuity in skilled facilities and rising levels of dependency in nonskilled assisted and supported living facilities and housing. In general, nursing homes provide two kinds of reimbursable Medicare service: subacute rehabilitation and skilled nursing. In both instances, admission to a nursing facility must have occurred within 30 days of hospitalization. It represents both the absence of adequate home supports and an illness-related decline in functional status. The goal is to return the patients to their previous level of function. However some proportions are never able to return to unsupported living. Increasingly, nursing homes have become the site of terminal care for patients without the resources for home hospice. Patients who are not Medicare eligible or have stayed beyond the 90 period must have another payor, usually it is Medicaid, some are self-pay.

The Myelodysplastic Syndromes (MDS) represent a heterogeneous group of bone marrow diseases of uncertain etiology characterized by a variable degree of cytopenias, predominantly but not exclusively anemia that is often macrocytic (1). The cytopenias reflect both ineffective hematopoiesis (marrow dysplasia or accelerated apoptosis) and increase in marrow leukemic blasts (2). In 85% of cases the marrow is normo to hypercellular but in 15% the marrow cellularity can be below 30% and, on occasion, below 15%, which raises the differential diagnosis with acquired aplastic anemia (3). In such instances it is necessary to depend on the morphologic identification of significant dysplasia of one or more of the myeloid cell lines or the identification of small clusters of blasts on a bone marrow biopsy. Over 50% of all cases occur in patients over the age of 70 years. Each year some 15,000 individuals will be diagnosed with MDS, although this may well be an underestimate. In a recent national survey of elderly patients with anemia (4) some 17% met the criteria for unexplained anemia and leucopenia or thrombocytopenia. This would amount to a prevalence of 163,000 individuals who might have MDS with a more careful evaluation.

This chapter explores the management of anemia in older cancer patients. Cancer is a disease of aging: more than 50% of all malignancies currently occur in the 12% of the population aged 65 and over; by the year 2030 older individuals are expected to account for 20% of the population and 70% of all cancer cases (1). Though not unique of older individuals, anemia is a common manifestation of cancer, especially of advanced cancer (2). The elderly are expected to suffer disproportionately of cancer-related anemia, because cancer becomes more common with age and because age itself is a risk factor for anemia (1–3).

Anemia is detrimental to cancer patients, because it compromises patient well-being, and it may increase the complications and reduce the benefits of antineoplastic treatment (2). Anemia of chronic inflammation (ACI) and of chemotherapy are the most common forms of anemia in cancer patients and both respond to pharmacological doses of erythropoietin (2, 4). The availability of a number of synthetic erythropoiesis-stimulating factors (ESF) that mimic the action of erythropoietin has allowed the correction of anemia in the majority of cancer patients.

After reviewing the pathogenesis of anemia we will examine the consequences of anemia for the older cancer patients and the benefits and potential risks of treatment with ESF.

As discussed extensively in this volume, anemia occurs with increasing frequency as people age. Curiously, a specific explanation for anemia is less readily apparent for older patients and approximately one-third of those with anemia over 65 years of age meet criteria for “Unexplained Anemia” (UA) as defined by Guralnik (1) and Artz (2). Although, by definition, those with kidney disease have an explanation for anemia and would not be considered to have UA, erythropoietin (EPO) insufficiency independent of overt renal excretory failure may be one component of this disorder. Certainly, other factors, including the coexistence of occult inflammatory disease, age-associated cytokine dysregulation (independent of inflammation) and androgen deficiency are also likely to contribute. In this chapter, EPO insufficiency will be considered in the context of anemia in general, and late-life UA in particular.

In a previous chapter, it has been shown that anemia is prevalent among older persons. This chapter will describe that anemia is not only prevalent, but also has important adverse clinical consequences. For instance, anemia has been associated with decreased physical function, elevated risks for falls and fractures, cognitive impairment, and increased mortality. Notably, these detrimental effects are observed not only in elderly individuals with severe reductions in Hb, but also in those with mild anemia or low-normal Hb levels. The chapter starts with describing why good physical function is an essential clinical geriatric outcome. Subsequent sections provide research findings that have linked anemia with poor physical function and other important related outcomes. The last section summarizes the most important findings and will discuss implications for health care and future research.